Pharmaceuticals which enhance neurotransmission of serotonin (5-HT) are useful for the treatment of many psychiatric disorders, including depression and anxiety. The first generation of non-selective serotonin-affecting drugs operated through a variety of physiological means which caused them to possess numerous undesired side effects. The more recently prescribed drugs, the selective serotonin reuptake inhibitors (SSRIs), act predominately by inhibiting 5-HT, which is released at the synapses, from being actively removed from the synaptic cleft via a presynaptic serotonin transport carrier. As SSRIs require several weeks before they exert their full therapeutic effect, this 5-HT blockade mechanism cannot fully account for their therapeutic activity. It is speculated that this two week induction which occurs before a full antidepressant effect is observed, is due to the involvement of the 5-HT1A autoreceptors which suppress the firing activity of the 5-HT neurons, causing a dampening of the therapeutic effect. Studies suggest that after several weeks of SSRI administration, a desensitization of the 5-HT autoreceptors occurs allowing a full antidepressant effect in most patients (See, e.g., Le Poul et al., Arch. Pharmacol. 352:141 (1995)). Hence, it is believed that overriding this negative feedback by using 5HT1A antagonists would potentially increase and accelerate the clinical antidepressant response. Recent studies by Artigas et al., Trends Neurosci., 19:378-383, (1996) suggest that a combination of 5-HT1A activity and inhibition of 5-HT uptake within a single molecular entity can achieve a more robust and fast-acting antidepressant effect.
The present invention relates to a new class of molecules which have the ability to act at the 5-HT1A autoreceptors and concommitantly with the 5-HT transporter. Such compounds are therefore potentially useful for the treatment of depression as well as other serotonin disorders.
U.S. Pat. No. 3,371,098 discloses sec. and tert. indolylethylamines useful as sedatives, anticonvulsants and analgesics.
U.S. Pat. No. 5,436,264 discloses N-aryloxyalkyl-tryptamine-like compounds of the following formula as alpha-1-adrenergic receptor antagonists for the treatment of cardiovascular disorders. ##STR2##
European Patent No. 0722 941 A2 discloses the preparation of a series of the following hetero-oxy alkanamines of formula for the treatment of depression and other conditions for which serotonin uptake inhibitors are normally used. ##STR3##
Japanese Patent Nos. 05255302 and 09040648 disclose the following compounds which are reported to be useful for the treatment of central nervous system-related diseases such as anxiety and depression. ##STR4##
U.S. Pat. No. 5,468,767 discloses a series of substituted indoles of the following formula for the treatment of disorders associated with dysfunction in serotonergic neurotrnsmission, including depression. ##STR5##